DRIVING BIOMEDICAL PROJECTS PROJECT SUMMARY Glycosaminoglycans (GAGs), such as heparin, heparan sulfate (HS), and chondroitin sulfate (CS), are naturally occurring polydisperse linear polysaccharides that are heavily O- and N-sulfated. The interaction between GAGs and proteins are critical for many biological processes including cell-cell and cell-matrix interactions, cell migration and proliferation, growth factor sequestration, chemokine and cytokine activation, microbial recognition and tissue morphogenesis during embryonic development. Hundreds of HS-binding proteins have been identified, but the oligosaccharide structures that mediate particular interactions have been defined in only a few cases due to the structural complexity of HS. Driving Biomedical Projects (DBPs) have been selected based on their potential impact on health-related issues, their ability to drive (or test) technology development within the Resource, and their compatibility with the current target area selected for our integrated technology resource. Five years ago the focus of the Resource shifted to glycosaminoglycan (GAG) - protein interactions. This is a challenging area raising problems associated with the characterization and isolation of segments from highly complex GAG chains, production and examination of proteins that are themselves glycosylated, and examination of the structure and biology of these systems in the context of large multi-protein complexes and cell-based assemblies. The technology needed to deal with these issues is multi- faceted and ranges from identification and production of GAG oligomers showing specificity in interaction (TR&D1), structural characterization of protein-GAG complexes at multiple scales (TR&D2) and cellular assays of biological effects (TR&D3). Any one problem can require integration of multiple technologies to reach a solution, and DBPs are in many cases chosen to exploit the integrated nature of our Resource. We consider the external investigator an integral part of this team, providing feedback on the success of technology applications and on opportunities for technology refinement. The GAG-protein interaction area is rich in potential impact. GAG-protein interactions play roles in migration of malignant cells, in normal and abnormal development of human organs, in our ability to respond to disease, in the regeneration of injured tissue, and in the transmission of signals needed for neuromuscular response. In addition to providing challenges for technology developments, DBPs are chosen to have impact on these diverse disease related issues. We feel that the projects selected adequately cover potential areas of impact and the need for technology drivers, while allowing each DBP to move forward on a reasonable timeframe.